The present invention relates to Liver X receptors (LXR). More particularly, the present invention relates to compounds useful as agonists for LXR, pharmaceutical formulations comprising such compounds, and therapeutic use of the same.
The orphan nuclear receptors, LXRα and LXRβ (collectively LXR) play a role in the maintenance of cholesterol balance. Peet et al., Curr. Opin. Genet Dev. 8:571-575 (1998). LXR is a transcription factor which regulates the expression of Cytochrome P450 7A (CYP7A). CYPP7A catalyses a key step in the conversion of cholesterol to bile acid, which process results in the removal of cholesterol from the liver.
In addition, LXR binds to the ATP Binding Cassette Transporter-1 (ABC1) (also known as ABCA 1) gene and increases expression of the gene to result in increased ABC1 protein. ABC1 is a membrane bound transport protein which is involved in the regulation of cholesterol efflux from extrahepatic cells onto nascent HDL particles. Mutations in the ABC1 gene are responsible for genetic diseases that result in the complete absence or low levels of HDL cholesterol and a concomitant highly increased risk of cardiovascular disease. See Brooks-Wilson et al., Nat. Genet. 22:336-345 (1999); Bodzioch et al., Nat. Genet. 22: 347-351 (1999); and Rust et al., Nat. Genet. 22:352-355 (1999). ABC1 knockout mice homozygous for the mutation in the ABC1 gene have virtually no plasma HDL whereas the heterozygotes produce 50% of the HDL of wild type animals. See, Orso et al., Nat. Genet. 24:192-196 (2000) and McNeish et al., Proc. Natl. Acad. Sci. USA 97:4245-4250 (2000). ABC1 knockout mice also show increased cholesterol absorption. See, McNeish et al., Proc. Natl. Acad. Sci. USA 97:4245-4250 (2000). Increased expression of ABC1 results in increased HDL cholesterol, decreased absorption of cholesterol, and increased removal of excess cholesterol from extrahepatic tissues, including macrophages.
Accordingly compounds which function as LXR agonists would be useful in methods of increasing ABC1 expression, increasing HDL cholesterol and treating LXR mediated diseases and conditions such as cardiovascular disease.